In the last few years the use of antioxidants has attained greater and greater importance, not only in industry, but also in agriculture, as well as in human and veterinary therapy. In the industrial field, and particularly in the rubber and plastic industry, there is an increasing demand for specific antioxidants compatible with different products and stabilizing to a high degree the advantageous physical properties of said products against oxidative damages. Antioxidants usable in the food industry and for medical purposes in human and veterinary therapy should satisfy several other requirements besides high activity, which, however, in some instances are in contravention with each other, or can only be combined with great difficulty. The most important special requirements which should be fulfilled by these antioxidants are the following: extremely low toxicity against living organisms, wide spectrum of activity, and high compatibility with a wide range of substances. A particularly important field where such antioxidants are used is the stabilization of foodstuffs and mixtures of foodstuffs containing, besides the easily decomposing organic substances and fats and oils sensitive to oxidation, also metal salts and trace elements, etc. catalyzing the oxidation processes. Such antioxidants have also particular value in the stabilizing of meat- and fish-meal and of other various products of the food industry, further in the stabilizing of medicines containing fats, oils and vitamins, which are extremely sensitive to oxidation processes. The antioxidants usable for the above purposes should exert their protective activity in a wide range of substances and they should maintain their effect also under conditions which normally lead to the decrease of activity.
In the last few years the demand for antioxidants of special effects has also been increased due to the recognition of the important role of oxidation processes, and, respectively, the harmful effects of peroxides formed in such oxidation processes displayed in living organisms. Such peroxides play an important role in the etiology of several pathological conditions of animals; e.g., in the exudative diathesis of poultries, liver diseases, yellowing of the fatty tissues in pigs, inhibiting the development of certain nematode larvae, etc. On the basis of these findings certain antioxidants have already been used with great success in the treatment of such pathological conditions. There was also recognized a causative relationship between the activity of antioxidants and of certain vitamins, first of all of vitamin E, and antioxidants have already been used with good results in the treatment of encephalomalacia of poultries. According to the recent results of investigations, antioxidants are also able to influence certain free radical reactions taking place in living tissues and in other biological systems, which play an important role in the aging processes, premature senescence of some organs, decomposition of biological macromolecules, pathological conditions followed by parenchymatic degeneration, as well as in heredodegenerative and autoimmune diseases, radiation sicknesses and in the formation of cancer-inducing substances, etc. These recent results of biological and biochemical investigations show also that the use of antioxidants attains a wider and wider importance not only in industry but also in human and veterinary therapy.
As a result of several extended investigations for preparing antioxidants usable in biological systems and also, for example, for the stabilizing of foodstuff mixtures, the use of N,N'-diphenyl-p-phenylenediamine /DPPD/ was proposed in the fifties. This compound, however, has not proved to be useful for the above purposes due to its toxicity, cancer-inducing effect and relatively low activity. There have also been proposed other compounds, namely, 2,6-di-tert.butyl-4-hydroxy-toluene /BHT/, a mixture of isomeric 2-tert.butyl-4-hydroxy-anisol and 3-tert. butyl-4-hydroxy-anisol /BHA/, mercapto-ethylamine, polyhydroxydiphenyl, gallic acid alkyl esters, and 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline /EMQ/ for the above purposes. Among these compounds first of all BHT and EMQ have found an extended use in the practice for the stabilizing of foodstuff mixtures and meat- and fish-meal, as well as for medical purposes in human and verterinary therapy. These compounds, however, do not meet the severe requirements with respect to the toxicity. According to the proposals of WHO/FAO Nutrition Meetings Report Series No. 4 A, B, C, WHO/FAODAU 67.29, only compounds having an LD.sub.50 value higher than 5 g./kg. body weight can be used in the food industry and for therapeutical purposes. The LD.sub.50 values of BHT and EMQ are, on the other hand, the following -- measured according to the Korber method, modified by Cornfield:
Bht-- 0.892 .+-. 0.12 g./kg. PA1 Emq-- 2.23 .+-. 0.30 g./kg. PA1 R.sub.1 represents hydrogen or a methyl group which may be attached in any of the free positions to the ring system with the exception of position 6, and PA1 n is 1, 2 or 3.
Besides the fact that the acute toxicity of these compounds exceeds the acceptable value, the investigations carried out on chronic toxicity closed also with unfavorable results. According to the results of investigations carried out in the Hungarian National Pharmaceutical Institute, EMQ, when administered to animals for a longer period in a dose of 0.56 g./kg. may cause appetite lowering, and lowers the gain in weight. Similar unfavorable results have been observed when administering EMQ into rats for 14 days in a dose of 0.50 g./kg.: the appetite of the animals was lowered; moreover an increase in size of the liver was observed. (See I. F. Gaunt et al.; Food and Cosmetic Tox., 3, 445-446; 1965.) It was also observed that when administering BHT, the cholesterol-synthesis in the liver as well as the endogenous epoxidation increases; moreover, this compound stimulates the endogenous production of fatty acids and .beta.-oxidation, and increases the gestation period. As an aftereffect, the appearance of anophthalmia was observed, indicating that the compound exerts a teratogeneous effect. (See G. Pascal et al.; Ann. Nutr. Alim., 23, 15-62; 1969.)
A further disadvantage of EMQ is that this compound is a liquid, which makes its use in heterogeneous phase more difficult and expensive. On the other hand, BHT has the disadvantage that in certain fields of application, e.g., in the prophylaxis and treatment of encephalomalacia of poultries, it has far lower activity than EMQ.
The above facts show unambiguously that even the best of the known antioxidants having an extended practical use, i.e., BHT and EMQ, cannot meet the severe requirements of nutrition, catering and therapy. Consequently, there still exists a great demand for active antioxidants usable for the above purposes.